This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Selenoproteins contain the trace element, selenium (Se), incorporated in the 21st amino acid selenocysteine. Selenoprotein P (SelP) has strong antioxidant properties and can chelate toxic metals. Targeted disruption of SelP results in neurological deficits including spatial memory deficiency. We recently reported that selenoprotein P (SelP) is associated with Alzheimer's pathology (Bellinger et al., J. Alzheimers Dis., 2008). This project will investigate the possible neuroprotective role for SelP and determine its importance in synaptic function and memory. We hypothesize that SelP protects neuronal function though direct antioxidant properties as well as supplying selenium for synthesis of other selenoproteins. We will test this hypothesis with the following aims: 1) determine the role of SelP in Alzheimer's pathology by characterizing SelP-expressing cells associated with plaques, and determining if SelP protects against amyloid toxicity, 2) determine the role of SelP in modulating synaptic changes by investigating synaptic physiology in SelP null mice, and 3) determine if brain-specific overexpression of SelP alters synaptic physiology. This research project will clarify the role of SelP in normal neurological function and its possible preventative role in neurodegenerative disorders.